The fact that the PRODH alteration studied in Gogos et al. leads to alterations in glutamate release, and this corresponds to deficits in associative learning and response to psychotomimetics, provides a nice parallel to the human condition. The Reiss paper examines humans with the 22q11.2 deletion, and shows that the COMT low-activity allele of this deletion syndrome correlates with cognitive decline, PFC volume, and development of psychotic symptoms. This is a nice addition to the Weinberger and Bilder papers about how COMT can lead to psychosis vulnerability.

I echo Jeff Lieberman's comment regarding previous reports of a weak association between the Val COMT functional allele and schizophrenia. Notably, the most recent meta-analysis (Munafo et al., 2005) shows no significant association. Even in 22q11.2 deletion syndrome (22qDS), our group (unpublished) and Murphy et al. (1999) have reported that there is no association between COMT genotype and schizophrenia, and Bearden et al. reported that Val-hemizygous patients performed significantly worse than Met-hemizygous patients on executive cognition ( 2004) and childhood behavioral problems (2005). Though important as an initial prospective study, there is a risk in the Gothelf et al. small sample size and multiple testing for type 1 errors. Certainly, there is little evidence, even in 22qDS, for COMT (or PRODH) as “key” risk factors for schizophrenia. There may be some evidence for small effects on cognitive or other measures. Regardless, there is not “extreme deficiency” in COMT activity in the many individuals with Met-hemizygosity in 22qDS, or Met-Met homozygosity in the general population.

Regarding the news item, there are a few widely held misconceptions about 22qDS. Our recent article (Bassett et al., 2005) shows that, accounting for ascertainment bias, the rate of schizophrenia was 23 percent, and congenital heart defects was 26 percent. Of the other 41 common lifetime features of 22qDS (found in 5 percent or more patients), neuromuscular palatal anomalies were common but overt cleft palate was so rare it did not meet inclusion criteria; intellectual disabilities ranged from severe mental retardation (rare) to average intellect (rare) with most patients falling in the borderline range of intellect; and on average, patients had nine of 43 common features. We propose clinical practice guidelines for adults with 22qDS which may be directly applicable to the 1-2 percent of patients with a 22qDS form of schizophrenia.